Structural Evidence for a Role of the Multi-functional Human Glycoprotein Afamin in Wnt Transport

Andreas Naschberger, Andrew Orry, Stefan Lechner, Matthew W. Bowler, Didier Nurizzo, Mislav Novokmet, Markus A. Keller, Gregor Oemer, Daniele Seppi, Martin Haslbeck, Kathrin Pansi, Hans Dieplinger, Bernhard Rupp

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23 Scopus citations


Afamin, a human plasma glycoprotein and putative transporter of hydrophobic molecules, has been shown to act as extracellular chaperone for poorly soluble, acylated Wnt proteins, forming a stable, soluble complex with functioning Wnt proteins. The 2.1-Å crystal structure of glycosylated human afamin reveals an almost exclusively hydrophobic binding cleft capable of harboring large hydrophobic moieties. Lipid analysis confirms the presence of lipids, and density in the primary binding pocket of afamin was modeled as palmitoleic acid, presenting the native O-acylation on serine 209 in human Wnt3a. The modeled complex between the experimental afamin structure and a Wnt3a homology model based on the XWnt8-Fz8-CRD fragment complex crystal structure is compelling, with favorable interactions comparable with the crystal structure complex. Afamin readily accommodates the conserved palmitoylated serine 209 of Wnt3a, providing a structural basis how afamin solubilizes hydrophobic and poorly soluble Wnt proteins. Naschberger et al. report the structure of afamin, a human plasma glycoprotein and transporter of hydrophobic molecules, thought to solubilize the hydrophobic Wnt signaling proteins. The authors’ model of the Wnt3a-afamin complex, based on the crystal structure of afamin and a homology model of Wnt3a, has implications for embryonic intercellular signaling.
Original languageEnglish (US)
Pages (from-to)1907-1915.e5
Number of pages191498094
Issue number12
StatePublished - Dec 5 2017
Externally publishedYes

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